Hydroxyaryl alicyclic carboxylic acids



Patented May 10, 1949 2,469,415 I C E HYDROXYARYL ALICYCLIC CARBOXYLIC ACIDS Erwin Schwenk, Montclair, N. J and Domenick Papa, Brooklyn, N. Y., assignors to Schering Corporation, Bloomfield, N. J a corporation of New Jersey No Drawing. Application January 30, 1947, Serial No. 725,266

7 Claims.

This invention relates to hydroxyaryl alicyclic alkene and alkane carboxylic acids and their metal and amine salts.

A general object of the invention is th production of new compounds suitable for use as chemotherapeutic agents.

We have found that the n -cycloalkene substituted acetic acids and their homologs and the corresponding isomeric cycloalkylidene carboxylic acids, having in the a-position to the carboxylic group either a methylene radical or the group =CI-I (in the case of substituted acetic acid), for example cyclohexenyl, cyclohexylidene, cyclopentenyl, cyclopentylidene, dihydronaphthyl and analogous acetic acids, and likewise th members of the acetic acid series substituted by terpene or terpene-like radicals having a double bond connected to the nuclear carbon atom linked to the acid group, can be condensed with an aromatic aldehyde wherein the double bond of the aldehyde group forms part of a conjugated doubl bond system, for example benzaldehyde, hydroxybenzaldehydes, cinnamaldehyde and hydroxycinnamaldehydes, to form dicyclic alkene carboxylic acids which may be subsequently saturated in the alkene chain and in the cycloalkene ill'lg.

Thus, p-hydroxybenzaldehyde, for example, may be condensed by the Perkin reaction or by modifications of the Perkin reaction, with a salt of cyclohexenyl acetic acid, such as the potassium or sodium salt, under anhydrous conditions in the presence of acetic anhydride, or in the form of the free acid and with the aid of a catalyst, for example, a tertiary amine like triethyl or tributyl amine, and the resulting a-A -cyclohexenyl)-p-hydroxycinnamic acid may be utilized as such or may be hydrogenated, as by means of hydrogen and Raney nickel catalyst, to yield a-cyclohexyla-(-hydroxyphenyl) propionic acid according to the following equation:

OOH OOH The products of the invention may be represented by the general formula wherein R. represents unsubstituted phenyl or hydroxyphenyl and R1 represents unsubstituted cycloalkyl groups or cycloalkyl groups substituted by lower alkyl groups, the cycloalkyl groups containing not less than five and not more than six carbon atoms in the ring, and Z represents hydrogen, alkali metal or alkaline earth metal.

The compounds of the invention, including the analogous compounds embodying heterocyclic rings such as thienyl, pyridyl and furyl, described in our co-pending application Ser. No. 629,916, filed November 20, 1945, have pronounced bactericidal properties particularly against gram negative organisms of the type commonly associated with intestinal infections. In general, the toxicity of the compounds is very low permitting the administration of large quantities of the compounds without any appreciable toxic reactions.

The compounds of the invention are also useful as intermediates for the production, by iodination, of useful amebicidal, bactericidal and X-ray contrast agents as described in our copending applications Serial No. 544,832, filed July 13, 1944, now abandoned, Serial No. 629,916, filed November 20, 1945, and Serial No. 722,084, filed Jan. 14, 1947, now abandoned.

EXAMPLE I a-(n -cyclohemenyl) cinnamic acid A mixture of 17.9 g. of anhydrous potassium- A -cyclohexenyl acetate and 10.6 g. of benzaldehyde is heated for 15-20 hours at C. with 100 cc. of acetic anhydride. The reaction mixture is then cooled to 60 C. and the excess acetic anhydride cautiously decomposed with water. The reaction mixture is poured on ice and the semisolid residue extracted with ether. The acidic fraction is isolated from the ether by extraction with sodium carbonate solution. On acidification of the sodium carbonate extracts the -(A cyclohexenyDcinnamic acid is obtained in the form of a pale yellow solid melting at-152" C. On recrystallization from a mixture of acetone and water the acid is obtained in the form of long, white, fine needles, melting at 156-157 C.

By the use of the isomeric anhydrous potassium cyclohexylidene acetate, this condensation yields the same product. It is advisable when using this acid to heat the reaction mixture for a few additional hours in order to secure a comparable yield.

EXAMPLE II e-cyclohexyl-fi-phenyl propionic acid in 200 cc. of 10% sodium hydroxide. The mix ture is heated to 90 C. and, with stirring, 1: 5 ggpf" EXAMPLE III a- (n -cycloherenyl) -p-.hydronaycinnamic acid a-cyclohezcyl-c-(p-hydromyphenyl) propz'onic acid Using either anhydrous ,potassiumeA wyclohexenyl acetate or anhydrous potassium cyclohfiylidene acetate with p-hydroxybenzaldehyd'e under the conditions as described in Example I, the a.-(A -CyClOheX6lly1) p-hydroxycinnamic acid is obtained after recrystallization from acetone and water as long, white needles melting at 195- 195 C.

When a-(n -cyclohexenyl) p-hydroxycinnamic acid is reduced as described in Example II, a quantitative yield of 13- (p-hydroxyphenyll-acyclohexylpropionic acid is obtained. Recrystallized from a mixture of acetone and water the substituted propionic acid is obtained as fine, White needles melting at 180--181 0.

EXAMPLE IV (A -cyclopentenyl) -p-hydro:cyci7mamic acid a -.cycl,opentyl ,8 (p-hydroscyphenyl) propionic acid Following the general procedure described for Example I, this acid is obtained by condensing either potassium cyclopentenyl or potassium cyclopentylidene acetate with p-hydroxybenzolde hyde. The product is obtained in the form of white needles which melt at 183 C. with decomposition.

The a-(n -cyclopentenyl) p-hydroxycinnamic acid when reduced as described in Example II yields the a-cylclopentyl-c-(p-hydroxyphenyl) propionic acid which melts-at 175-178 C. Recrystallized from acetone and Water the product is obtained as white needles melting at 180-181 C.

EXAMPLE V a- (a-fi-methoay-3,4-dihydronaphthalene) .-.p hydrorycinnamic acid w-(G-methOmytetTaZyZ-I) c (p-hydroscyp'henyl) propiom'c acid Using the general procedure described in Example I, 12.8 g. of anhydrous potassium-fi-meth oxy-l-tetralidene acetate, 6.1 g. of p-hydroxybenzaldehyde and 100 cc. of acetic anhydride are heated for to hours at 105-110 C. The condensation product is isolated by the ethersodium carbonate extraction method, and after several recrystallizations from benzene and peatroleum ether it melts at 189-191 C. with decomposition.

Five grams of the above substituted cinnamic acid, when reduced with Raneys alloy and aqueous alkali, yields the a-(6-methoxytetralyl-1)- B- (p-hydroxyphenyl) 'propionic acid, which. melts at 168-1743 Recrystallization from aqueous alcohol gives the acid in the form of fine, white needle smelting at 182-1-83.

The mixture is stirred for EXAMPLE The synthesis as outlined in Examples I to V .can be modified to avoid the use of the anhydrous alkali salts. ifree'acid, cyclohexenyl, cyclopentenyl, and other alicyclic acetic acids with the appropriate aromatic aldehyde together with suitable catalysts, .i. .e., triethyl amine, anhydrous sodium or potasslum acetate, anhydrous potassium carbonate,

Substitution of the cyclohexenyl acetic acid by cyclohexylidene acetic acid gives a comparable yield, but requires a few additional hours of heat ing. Substitution of the triethyl amine by anhydrous potassium acetate likewise gives a good yield in the condensation.

In place of cyclohexenyl acetic acid or of cyclohexylidene acetic acid, and the similarly substituted homologous acids, there may be employed acetic acid and its homologues substituted. by .cyclohexanol, wherein both the hydroxyl and the acid group are joined to the same nuclear car.- bon. During the course of the reaction of such a cyclohexanol acetic acid or its ester with .an aromatic or heterocyclic aldehyde in the presence of acetic anhydride (or other saturated aliphatic acid anhydride), and of a catalyst like trimethylamine, dehydration of the cyclohexanol acetic acid or ester takes place with the formation of either or both of N-cyclohexenyl acetic acid and cyclohexylidene acetic acid, acids or esters. It is desirable to use three molar equivalentsof the catalyst.

EXAMPLE VII a-(n -cycloherenyl) p-hydroacycmnamic acid Ninety-three grams (0.5 m.) of ethylcyclohexanol-l acetate, 61 gm. (0.5 m.) f p-hydroxybenzaldehyde, 150 gm. (1.5 m.) of triethylam-ine and 300 cc. of acetic anhydride are heated, pref-- erably with stirring, for 25-35 hours at C. At the end of the heating period the reaction mixture is coo-led to 60 and the excess acetic anhydride cautiously decomposed by the addition of Water. The resulting solution is poured into ice and the product extracted with ether. The ether solution is washed free of acetic acid, the ether evaporated, and the resulting residue, Which is principally the ester of the condensation product, is saponified with either aqueous or alcoholic alkali. The saponified solu. tion is then treated with carbon dioxide in order to convert the alkali to bicarbonate. treatment the solution is heated, treated with charcoal, and filtered. Upon acidification the a-(n -cyclohexenyl) p-hydroxycinnamic acid is precipitated and filtered. The product obtained melts at 191-193 C. after recrystallization from a mixture of acetone andwater.

In place of the triethylamine, other organic amines may be used for catalyzing the condensation-,-as Well as metallicsalts such as sodium and potassium'acetate.

a- (Cyclohexyl) -c- (p-hydroxyphenyl) propionic acid is obtained from am -cyclohexenyh-p-hydroxycinnamic acid byreducing 10 grams of the latter with Raneys alloy and aqueous alkali} as This modification uses the or homologous After this 1 described in the Journal of Organic Chemistry, 9,175 (1944). The substituted propionic acid is isolated in the usual manner and after recrystallization from aqueous acetone melts at 180- 181 C.

EXAMPLE VIII oz- (3,3,5 -trz'methylcyclohemyl) -,3- (ya-hydroxyphenyl) propionic acid By the usual Reformatsky reaction between trimethylcyclohexanone, ethylbromacetate, zinc, and a mixture of benzene and toluene as solvent, there is obtained the ethyl 3,3,5-trimethylcyclohexanol-l acetate which boils at 103-104 (C./2 mm. Many variations may be made in this procedure; for example, choice of solvents, type of zinc, etc. We have found that by using granular zinc in a 50-50 mixture of benzene and toluene, good yields of the ethyl trimethylcyclohexanol acetate are obtained.

Saponification of the above ethyl acetate compound with alcoholic sodium hydroxide yields the 3,3,B-trimethylcyclohexanol-1 acetic acid, which, after recrystallization from petroleum ether, melts at 116ll7 C.

When the ethyl acetate derivative described above is dehydrated by any of the usual agents, for example, anhydrous HCl, fused potassium bisulfate, etc., there is obtained the unsaturated compound, ethyl 3,3,5-trimethylcyclohexylidene acetate or the ethyl 3,3,5-trimethy1-A -cyclohexenyl acetate. The type of dehydrating agent used will determine which one of these two isomers is secured. The unsaturated compounds boiled at 76 C./1 mm. When these compounds are saponified with alcoholic sodium hydroxide, there is obtained the 3,3,5-trimethylcyclohexylidene acetic acid or the isomeric A -3,3,5-trimethylcyclohexenyl acetic acid. One of thes products which we have isolated, and which probably is the hexylidene compound, melts at 80-81" C. after recrystallization from petroleum ether.

B condensing 20 gm. of the trimethylcyclohexanol-l acetic acid with 12 gm. of p-hydrox benzaldehyde in the presence of 150 cc. of acetic anhydride with 40 cc. of triethylamine as catalyst, there is obtained, after Working up the reaction mixture in the normal manner, a-(A -3,3,5- trimethylcyclohexenyl)-p-hydroxycinnamic acid. Satisfactory yields in this reaction are obtained when the reaction mixture described above is heated for a period of 25-35 hours at 100-110 C. The substituted cinnamic acid, after recrystallization from a mixture of methyl alcohol and water, melts at 181-182 C.

The substituted cinnamic acid, when reduced with Raneys alloy and aqueous alkali as mentioned in a previous example, yields the a-(3,3,5- trimethylcyclohexyl) -,8- (p-hydroxyphenyl) propionic acid. This substituted propionic acid, after recrystallization from aqueous alcohol, melts at 189189.5 C.

EXAMPLE IX Ethyl (3-methyl-6-isopropylcyclohemanol-l) acetate methylisopropylcyclohexanol ethyl acetate as a H pale yellow oil boiling at 107/1 mm.

By a series of transformations similar to that described under Example VIII, this cyclohexanol ethyl acetate compound can be converted into the corresponding acids and dicyclic condensation products.

The above-described acids can be converted by the usual reactions into the corresponding salts; for example, the alkali metal salts, such as sodium and potassium, the alkaline earth metal salts, such as those of calcium and magnesium; and the amine salts, like those of mono-, di-, and triethyl amines, dimethylamino ethanol, and the like.

This application is a continuation-in-part of our application Serial No. 544,831, filed July 13, 1944, and contains subject matter in common with our applications Serial No. 544,832, filed July 13, 1944, Serial No. 629,916, filed November 20, 1945, and Serial No. 722,084, filed January 14, 1947.

We claim:

1. Compounds of the general formula wherein R is selected from the group consisting of unsubstituted phenyl and hydroxyphenyl and R1 is selected from the group consisting of unsubstituted cycloalkyl groups and cycloalkyl groups substituted by lower alkyl groups, the cycloalkyl groups containing not less than five and not more than six carbon atoms in the ring, and Z is selected from the group consisting of hydrogen, alkali metal and alkaline earth metal.

2. Compounds of the general formula wherein R. is a hydroxyphenyl group and R1 is a cycloalkyl group having not less than five and not more than six carbon atoms in the ring.

3. Compounds of the general formula of claim 2 wherein R is a hydroxyphenyl group and R1 is a cycloalkyl group having six carbon atoms.

4. Compounds of the general formula of claim 2 wherein R is a hydroxyphenyl group and R1 is a cycloalkyl group having five carbon atoms. umn 4057 (1943), Can. J. Research 21 B, pages 5. a-cyclohexyl-B-(p-hydroxyphenyl) propionic acid and the alkali and alkaline earth salts thereof.

6. a-cyclopentyl-p-(pl-hydroxyphenyl) propionic acid and the alkali and alkaline earth salts thereof.

7. a (3,3,5 trimethylcyclohexyl) ,6 (p-hydroxyphenyl) propionic acid.

ERWIN SCHWENK. DOMENICK PAPA.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Natelson et al. May 14, 1946 OTHER REFERENCES Number Certificate of Correction Patent No. 2,469,415. May 10,1949.

ERWIN SOHWENK ET AL.

It is hereby certified that error appears in the printed specification of the abovenumbered patent requiring correction as follows:

Column 6, line 49, strike out the syllable and words umn 4057 (1943), Can. J. Research 21 B, pages;

and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 4th day of October, A. D. 1949.

THOMAS F. MURPHY,

Assistant Oommz'ssioner of Patents. 

